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Josep Dalmau - One of the best experts on this subject based on the ideXlab platform.

  • an update on anti nmda Receptor Encephalitis for neurologists and psychiatrists mechanisms and models
    Lancet Neurology, 2019
    Co-Authors: Josep Dalmau, Maarten J Titulaer, Frank Leypoldt, Thais Armangue, Jesus Planaguma, Marija Radosevic, Francesco Mannara, Christian Geis, Eric Lancaster, Myrna R Rosenfeld
    Abstract:

    The identification of Anti-NMDA Receptor (NMDAR) Encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex Encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

  • a score that predicts 1 year functional status in patients with anti nmda Receptor Encephalitis
    Neurology, 2019
    Co-Authors: Ramani Balu, Josep Dalmau, Lindsey Mccracken, Francesc Graus, Eric Lancaster, Maarten J Titulaer
    Abstract:

    Objective To construct a grading score that predicts neurologic function 1 year after diagnosis of Anti-NMDA Receptor (NMDAR) Encephalitis. Methods Three hundred eighty-two patients with detailed information and functional status at 1 year were studied. Factors associated with poor status (defined as modified Rankin Scale score ≥3) were identified and incorporated into a multivariate logistic regression model. This model was used to develop a 5-point prediction score, termed the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Results Intensive care unit admission ( p 4 weeks ( p = 0.012), lack of clinical improvement within 4 weeks ( p p = 0.001), central hypoventilation ( p p p = 0.027), and abnormal MRI ( p = 0.002) were associated with 1-year functional status in univariate analysis. Intensive care unit admission, treatment delay >4 weeks, lack of clinical improvement within 4 weeks, abnormal MRI, and CSF white blood cell count >20 cells/μL were independent predictors for outcome in multivariate regression modeling. These 5 variables were assigned 1 point each to create the NEOS score. NEOS score strongly associated with the probability of poor functional status at 1 year (3% for 0 or 1 point to 69% for 4 or 5 points, p Conclusions The NEOS score accurately predicts 1-year functional status in patients with Anti-NMDAR Encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.

  • nmda Receptor Encephalitis and other antibody mediated disorders of the synapse the 2016 cotzias lecture
    Neurology, 2016
    Co-Authors: Josep Dalmau
    Abstract:

    Investigations during the last 10 years have revealed a group of disorders mediated by antibodies against ion channels and synaptic Receptors, which cause both neurologic and psychiatric symptoms. In this review, I discuss the process of discovery and immunologic triggers of these disorders, and use Anti-NMDA Receptor Encephalitis to emphasize the importance of understanding the underlying physiopathologic mechanisms in those diseases. A better knowledge of these mechanisms reveals points of convergence with other disorders (e.g., schizophrenia), suggests treatment strategies beyond immunotherapy, and is helping us understand how memories are formed and retrieved.

  • anti nmda Receptor Encephalitis autoimmunity and psychosis
    Focus (American Psychiatric Publishing), 2016
    Co-Authors: Matthew S Kayser, Josep Dalmau
    Abstract:

    Anti-N-methyl-d-aspartate Receptor (NMDAR) Encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms – and in particular psychosis – early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in Anti-NMDAR Encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.(Reprinted with permission from Schizophrenia Research 2013; 176:36–40)

  • anti nmda Receptor Encephalitis autoimmunity and psychosis
    Schizophrenia Research, 2016
    Co-Authors: Matthew S Kayser, Josep Dalmau
    Abstract:

    Anti-N-methyl-d-aspartate Receptor (NMDAR) Encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms - and in particular psychosis - early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in Anti-NMDAR Encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.

Maarten J Titulaer - One of the best experts on this subject based on the ideXlab platform.

  • an update on anti nmda Receptor Encephalitis for neurologists and psychiatrists mechanisms and models
    Lancet Neurology, 2019
    Co-Authors: Josep Dalmau, Maarten J Titulaer, Frank Leypoldt, Thais Armangue, Jesus Planaguma, Marija Radosevic, Francesco Mannara, Christian Geis, Eric Lancaster, Myrna R Rosenfeld
    Abstract:

    The identification of Anti-NMDA Receptor (NMDAR) Encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex Encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

  • a score that predicts 1 year functional status in patients with anti nmda Receptor Encephalitis
    Neurology, 2019
    Co-Authors: Ramani Balu, Josep Dalmau, Lindsey Mccracken, Francesc Graus, Eric Lancaster, Maarten J Titulaer
    Abstract:

    Objective To construct a grading score that predicts neurologic function 1 year after diagnosis of Anti-NMDA Receptor (NMDAR) Encephalitis. Methods Three hundred eighty-two patients with detailed information and functional status at 1 year were studied. Factors associated with poor status (defined as modified Rankin Scale score ≥3) were identified and incorporated into a multivariate logistic regression model. This model was used to develop a 5-point prediction score, termed the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Results Intensive care unit admission ( p 4 weeks ( p = 0.012), lack of clinical improvement within 4 weeks ( p p = 0.001), central hypoventilation ( p p p = 0.027), and abnormal MRI ( p = 0.002) were associated with 1-year functional status in univariate analysis. Intensive care unit admission, treatment delay >4 weeks, lack of clinical improvement within 4 weeks, abnormal MRI, and CSF white blood cell count >20 cells/μL were independent predictors for outcome in multivariate regression modeling. These 5 variables were assigned 1 point each to create the NEOS score. NEOS score strongly associated with the probability of poor functional status at 1 year (3% for 0 or 1 point to 69% for 4 or 5 points, p Conclusions The NEOS score accurately predicts 1-year functional status in patients with Anti-NMDAR Encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.

  • immunoglobulin g antibodies to the n methyl d aspartate Receptor are distinct from immunoglobulin a and immunoglobulin m responses
    Annals of Neurology, 2015
    Co-Authors: Eric Lancaster, Jerome Honnorat, Maarten J Titulaer, Frank Leypoldt, Patrick Waters, Markus Reindl, Romana Hoftberger
    Abstract:

    Dahm and colleagues recently reported that approximately 10% of patients and healthy individuals may have IgA, IgG or IgM autoantibodies to the NR1 subunit of the NMDA Receptor in their serum (“Seroprevalence of autoantibodies against brain antigens in health and disease”).1 They specifically conclude that “the obtained data may serve as a reference for clinicians advising caution with respect to any conclusions on a causal association of serum antibody with brain disease.” In respect to NMDAR Encephalitis their interpretation of this data is misleading and may cause confusion for readers. The prevalent responses measured in the current paper were mostly IgM and IgA antibodies, all measured only in serum, and often at lower serum titer (1:10) than reported as cut-off for Anti-NMDAR Encephalitis (1:40).2 There are no data to suggest an association between IgA or IgM antibodies with NMDAR Encephalitis and their detection has no utility for diagnosing this disease. Age-related seroprevalence of control cohorts was previously shown to be around 10%. Whether the presence of high titers of these IgA or IgM antibodies in CSF associates with disease (e.g. slow cognitive decline)3 remains to be elucidated. As the authors noted, IgG antibodies to surface epitopes of the Receptor are associated with Anti-NMDA Receptor Encephalitis. Indeed, IgG NMDAR antibodies were only detected in this study in 34/2533 (1.3%) and 20/1703 (1.2%) of the “disease group” or “healthy control group”, respectively. This is within the known rate of false positive results if testing is done in serum samples only without comprehensive assessment of CSF samples.2, 4 IgG NMDAR antibodies to surface epitopes of the Receptor measured in CSF are highly specific for a characteristic autoimmune neurological syndrome that has specific tumor associations (ovarian teratoma), evidence of brain inflammation in many patients (based on MRI and/or CSF analysis), characteristic EEG findings in some patients (extreme delta brush) and an established response to immunotherapy. These antibodies are also present in most patients' serum but are more specifically measured in CSF and many patients show evidence of intrathecal synthesis of the antibodies.2 They cause cross-linking and internalization of the NMDA Receptor on cultured neurons.5 Therefore grouping these three antibody classes together and making general conclusions is not accurate or appropriate. We hope that clarification and emphasis of these important differences can alert clinicians and prevent misinterpretation of test results and potential over- or under-treatment of patients.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

Myrna R Rosenfeld - One of the best experts on this subject based on the ideXlab platform.

  • an update on anti nmda Receptor Encephalitis for neurologists and psychiatrists mechanisms and models
    Lancet Neurology, 2019
    Co-Authors: Josep Dalmau, Maarten J Titulaer, Frank Leypoldt, Thais Armangue, Jesus Planaguma, Marija Radosevic, Francesco Mannara, Christian Geis, Eric Lancaster, Myrna R Rosenfeld
    Abstract:

    The identification of Anti-NMDA Receptor (NMDAR) Encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex Encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • late onset anti nmda Receptor Encephalitis
    Neurology, 2013
    Co-Authors: Maarten J Titulaer, Myrna R Rosenfeld, Abiguei Torrents, Lindsey Mccracken, Rita J Balicegordon, Inigo Gabilondo, Takahiro Iizuka, Izumi Kawachi, Luis Bataller, Francesc Graus
    Abstract:

    Objective: To describe the clinical features and outcome of anti–NMDA Receptor (NMDAR) Encephalitis in patients ≥45 years old. Method: Observational cohort study. Results: In a cohort of 661 patients with Anti-NMDAR Encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18–44 years), older patients were more often male (45% vs 12%, p p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0–2 at 2 years, 60% vs 80%, p p = 0.0001), early treatment (OR 0.60, CI 0.47–0.78, p p p p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up. Conclusions: Anti-NMDAR Encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

  • anti nmda Receptor Encephalitis and other synaptic autoimmune disorders
    Current Treatment Options in Neurology, 2011
    Co-Authors: Myrna R Rosenfeld, Josep Dalmau
    Abstract:

    Synaptic autoimmunity may result in a wide variety of symptoms, including catatonia, psychosis, movement disorders, short-term memory deficits, and refractory seizures, so these patients are seen by a wide spectrum of practitioners, who need to be aware of these disorders. In some cases, these disorders occur as a paraneoplastic manifestation of an associated cancer. However, in contrast to the well-known paraneoplastic neurologic disorders of the central nervous system that predominate in older individuals, these novel disorders often affect children and young adults. Additionally, for some syndromes, the presence of a tumor does not necessarily indicate a poor prognosis. Successful treatment of the tumor and immunotherapy often result in recovery, supporting the use of surgery for severely ill patients. In all syndromes, deficits may be reversible despite the duration or severity of symptoms. For example, patients with anti–NMDA-Receptor Encephalitis who had been in a coma or ventilated for 6–10 months have had full recovery after appropriate treatment.

Frank Leypoldt - One of the best experts on this subject based on the ideXlab platform.

  • an update on anti nmda Receptor Encephalitis for neurologists and psychiatrists mechanisms and models
    Lancet Neurology, 2019
    Co-Authors: Josep Dalmau, Maarten J Titulaer, Frank Leypoldt, Thais Armangue, Jesus Planaguma, Marija Radosevic, Francesco Mannara, Christian Geis, Eric Lancaster, Myrna R Rosenfeld
    Abstract:

    The identification of Anti-NMDA Receptor (NMDAR) Encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex Encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.

  • immunoglobulin g antibodies to the n methyl d aspartate Receptor are distinct from immunoglobulin a and immunoglobulin m responses
    Annals of Neurology, 2015
    Co-Authors: Eric Lancaster, Jerome Honnorat, Maarten J Titulaer, Frank Leypoldt, Patrick Waters, Markus Reindl, Romana Hoftberger
    Abstract:

    Dahm and colleagues recently reported that approximately 10% of patients and healthy individuals may have IgA, IgG or IgM autoantibodies to the NR1 subunit of the NMDA Receptor in their serum (“Seroprevalence of autoantibodies against brain antigens in health and disease”).1 They specifically conclude that “the obtained data may serve as a reference for clinicians advising caution with respect to any conclusions on a causal association of serum antibody with brain disease.” In respect to NMDAR Encephalitis their interpretation of this data is misleading and may cause confusion for readers. The prevalent responses measured in the current paper were mostly IgM and IgA antibodies, all measured only in serum, and often at lower serum titer (1:10) than reported as cut-off for Anti-NMDAR Encephalitis (1:40).2 There are no data to suggest an association between IgA or IgM antibodies with NMDAR Encephalitis and their detection has no utility for diagnosing this disease. Age-related seroprevalence of control cohorts was previously shown to be around 10%. Whether the presence of high titers of these IgA or IgM antibodies in CSF associates with disease (e.g. slow cognitive decline)3 remains to be elucidated. As the authors noted, IgG antibodies to surface epitopes of the Receptor are associated with Anti-NMDA Receptor Encephalitis. Indeed, IgG NMDAR antibodies were only detected in this study in 34/2533 (1.3%) and 20/1703 (1.2%) of the “disease group” or “healthy control group”, respectively. This is within the known rate of false positive results if testing is done in serum samples only without comprehensive assessment of CSF samples.2, 4 IgG NMDAR antibodies to surface epitopes of the Receptor measured in CSF are highly specific for a characteristic autoimmune neurological syndrome that has specific tumor associations (ovarian teratoma), evidence of brain inflammation in many patients (based on MRI and/or CSF analysis), characteristic EEG findings in some patients (extreme delta brush) and an established response to immunotherapy. These antibodies are also present in most patients' serum but are more specifically measured in CSF and many patients show evidence of intrathecal synthesis of the antibodies.2 They cause cross-linking and internalization of the NMDA Receptor on cultured neurons.5 Therefore grouping these three antibody classes together and making general conclusions is not accurate or appropriate. We hope that clarification and emphasis of these important differences can alert clinicians and prevent misinterpretation of test results and potential over- or under-treatment of patients.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • herpes simplex virus 1 Encephalitis can trigger anti nmda Receptor Encephalitis case report
    Neurology, 2013
    Co-Authors: Frank Leypoldt, Maarten J Titulaer, Esther Aguilar, Janine Walther, Marlene Bonstrup, Stefanie Havemeister, Bianca Teegen, Marc Lutgehetmann, Michael Rosenkranz, Tim Magnus
    Abstract:

    Relapsing symptoms post herpes simplex virus 1 (HSV) Encephalitis (HSVE) usually occur a few weeks after viral therapy and represent either 1) a true viral relapse of HSVE (CSF PCR positive for HSV, new necrotic lesions on brain MRI, and response to acyclovir therapy) or 2) a disorder postulated to be immune-mediated (CSF negative for HSV, no new necrotic lesions, and no response to acyclovir).1,2 It has been suggested that this immune-mediated disorder may be related to NMDA Receptor (NMDAR) antibodies,3 and we recently reported a child in whom relapsing symptoms post HSVE were the presentation of Anti-NMDAR Encephalitis.4 We report an adult with this disorder, demonstrate that synthesis of NMDAR antibodies began after HSVE, and show that relapsing symptoms were due to steroid-responsive Anti-NMDAR Encephalitis.

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  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • antibody titres at diagnosis and during follow up of anti nmda Receptor Encephalitis a retrospective study
    Lancet Neurology, 2014
    Co-Authors: Nuria Gresaarribas, Amy J Gleichman, Maarten J Titulaer, Abiguei Torrents, Esther Aguilar, Lindsey Mccracken, Frank Leypoldt, Rita J Balicegordon, Myrna R Rosenfeld
    Abstract:

    Summary Background Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with Anti-NMDA Receptor Encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA Receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with Anti-NMDA Receptor Encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA Receptor mutants. Findings We analysed samples from 250 patients with Anti-NMDA Receptor Encephalitis and 100 control participants. All 250 patients had NMDA Receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA Receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.

  • Anti-NMDA Receptor Encephalitis Antibody Binding Is Dependent on Amino Acid Identity of a Small Region within the GluN1 Amino Terminal Domain
    Journal of Neuroscience, 2012
    Co-Authors: Amy J Gleichman, Lynn A. Spruce, Steven H Seeholzer, Josep Dalmau, D. R. Lynch
    Abstract:

    Anti-NMDA Receptor (NMDAR) Encephalitis is a newly identified autoimmune disorder that targets NMDARs, causing severe neurological symptoms including hallucinations, psychosis, and seizures, and may result in death (Dalmau et al., 2008). However, the exact epitope to which these antibodies bind is unknown. A clearly defined antigenic region could provide more precise testing, allow for comparison of immunogenicity between patients to explore potential clinically relevant variations, elucidate the functional effects of antibodies, and make patients' antibodies a more effective tool with which to study NMDAR function. Here, we use human CSF to explore the antigenic region of the NMDAR. We created a series of mutants within the amino terminal domain of GluN1 that change patient antibody binding in transfected cells in stereotyped ways. These mutants demonstrate that the N368/G369 region of GluN1 is crucial for the creation of immunoreactivity. Mass spectrometry experiments show that N368 is glycosylated in transfected cells and rat brain regions; however, this glycosylation is not directly required for epitope formation. Mutations of residues N368/G369 change the closed time of the Receptor in single channel recordings; more frequent channel openings correlates with the degree of antibody staining, and acute antibody exposure prolongs open time of the Receptor. The staining pattern of mutant Receptors is similar across subgroups of patients, indicating consistent immunogenicity, although we have identified one region that has a variable role in epitope formation. These findings provide tools for detailed comparison of antibodies across patients and suggest an interaction between antibody binding and channel function.

  • cellular and synaptic mechanisms of anti nmda Receptor Encephalitis
    The Journal of Neuroscience, 2010
    Co-Authors: Ethan G Hughes, Amy J Gleichman, Josep Dalmau, Xiaoyu Peng, David A Lynch, Meizan Lai, Lei Zhou, Ryan Tsou, Thomas D Parsons, Rita J Balicegordon
    Abstract:

    We recently described a severe, potentially lethal, but treatment-responsive Encephalitis that associates with autoantibodies to the NMDA Receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface Receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA Receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate Receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with Anti-NMDAR Encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate Receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with Anti-NMDAR Encephalitis.

  • anti nmda Receptor Encephalitis case series and analysis of the effects of antibodies
    Lancet Neurology, 2008
    Co-Authors: Josep Dalmau, Amy J Gleichman, Myrna R Rosenfeld, Rita J Balicegordon, Ethan G Hughes, Jeffrey E Rossi, Xiaoyu Peng, Scott K Dessain, David A Lynch
    Abstract:

    Summary Background A severe form of Encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA Receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA Receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with Encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-Receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA Receptors and NMDA-Receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with Anti-NMDA-Receptor Encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.